Peripheral arterial disease (PAD) affects nearly 8 million people and costs >$21B in the U.S. per year. With reduced blood supply to their legs, some patients experience calf pain or fatigue with walking. Although PAD can be reliably detected by a low ankle blood pressure, and anatomic imaging (MRI or CT) of the narrowing arteries, to select the best treatment approach, we need a non-invasive test to assess calf-muscle function. In this project, we propose to use high-resolution magnetic resonance imaging (MRI) to measure blood perfusion in different groups of calf muscle, and repeat the measurement after a low-load and a high-load exercise of calf muscle. This stress-rest imaging approach is standard of care for evaluation of coronary artery disease (CAD), and has never been successfully applied to PAD. Our preliminary results show distinct patterns of muscle perfusion between healthy and PAD patients, and thus great promise of the technique. In this 4-year project, we will first refine the perfusion imaging method, verify its reproducibility, and then compare the calf muscle perfusion measures in PAD patients against healthy age-matched healthy controls. This comparison will test the feasibility of detecting functional abnormality in PAD patients. After the baseline scans, the PAD patients will undergo a 12-week supervised exercise therapy, and then a post-therapy MRI scan. Comparison of the pre- and post-therapy measurement will indicate how the therapy improves the calf-muscle perfusion, and how this perfusion change correlates with increase in patient?s walking ability. The long term goals of this project are to develop an improved diagnostic test for patients with PAD to predict who will benefit from therapeutic intervention. The stress-rest perfusion studies of calf muscle can be performed in conjunction with routine peripheral MRA to assess the functional significance of vascular stenosis. As with the routinely performed cardiac stress imaging methods, improved functional measures of calf perfusion should also prove useful in the testing and development of improved therapeutic approaches.